Alkylpyrrole carboxylic acids and derivatives thereof



United States PatentOffice p,

2,797,228v Patented June 25, 1957 ALKYLPYRROLE CARBOXYLIC ACIDS AND DERIVATIVES THEREOF John S. Webb, Warren Township, Somerset County, N. J Coy W. Waller, Nanuet, N. Y., and Martin J. Weiss, Teaneck, N. .L, assignors to American Cyanamid Compauy, New York, N. Y., a corporation of Maine No Drawing. Application August 2, 1955, Serial No. 526,059

6 Claims. (Cl. zen-326.3

in which R is an alkyl radical containing to 10 carbon atoms, R is hydrogen, lower alkyl or an alkali metal radical and R is hydrogen or an aroyl radical. As the compounds of the present invention contain an amino or substituted amino group in the 4 position they also form acid addition salts such as the hydrochloride, hydrobromide, hydroiodide and the like.

The compounds of the present invention are crystalline solids having a definite melting point. They are soluble in the usual organic solvents such as alcohol, pyridine, dimethylformamide, etc. In the form of their salts they are water soluble.

These compounds can be prepared by diflierent methods. One method is by reduction of the corresponding nitro compounds as shown hereinafter in the examples.

The present compounds show unusual activity as antibacterial agents. When tested against the organisms Mycobacterium Sp. 607 and Sarcina lutea the following results were obtained.

TABLE I.-ANTI-BACTERIAL ACTIVITY OF- [Minimal inhibitory concentration M/ml.).]

The figures given above are the minimum concentrations of the test compound required to completely inhibit the growth of the organisms and are expressed in micromoles per milliliter. Thus the smaller the value the more active is the compound. From these results it can be seen that the most active compound of the present series, ethyl 4-amino-1 nhexyl-2 pyrrolecarboxylate (i. e. R=CsH1s-) is twenty to forty times more potent in stopping bacterial growth than for example, ethyl 4- amino-l-methyl-2-pyrrolecarboxylate (i. e. R=CH3). The other members of the present compounds while not as active as the l-hexyl compounds all have an antibacterial activity at least several times more active than the l-methyl compound.

The compounds of the present invention are usually obtained in the form of their esters. On (alkaline hydrolysis the esters give acids which are amphoteric. The alkali metal salts of the acids are prepared by treating the acids with, for example, alkali metal hydroxides.

The following examples illustrate in detail the preparation of alkylpyrro'le carboxylic acids, esters and alkali metal salts thereof.

Example 1.Ethyl 4-amin0-1-n-hexyl-2-pyrrolecarboxylate hydrochloride Ethyl 4-nitro-2-pyrrolecarboxylate, 20 parts, is added to a solution of sodium methyl ate, 7 parts, in absolute ethanol, 40 parts. To this solution is added 56 parts of n-hexyl bromide and the mixture refluxed for 30 minutes. On standing overnight sodium bromide separates which is removed by filtration. The filtrate is then cooled to l0 C. for 1 hour and the crystals which form are collected and dried. The yield is 11 parts of ethyl l-n-hexyl- 4-nitro-2-pyrrolecarboxyl-ate having a melting point of 42.6-43.6 C.

The above nitro compound, 11 parts, is dissolved in '80 parts of absolute ethanol, 1 part of 10% palladium on charcoal catalyst is added and the mixture is shaken with hydrogen under pressure. After the rapid adsorption of hydrogen is over the catalyst is removed by filtration and dry, hydrogen chloride passed into the filtrate during cool ing to 0 C. The solution is then concentrated to dryness under reduced pressure and the resulting crystals separated from some oily material by filtration, washed with petroleum ether and dried to yield 4.9 parts of ethyl 4- amino-l-n-hexyl-2-pyrrolecarboxylate hydrochloride having a melting point of 125.3427 C.

Example 2 By following the same general procedure of Example 1 and using equi-molecular amounts of the appropriate alkyl bromides in place of n-hexyl bromide, the compounds summarized in the following table are prepared:

Melting Point R X=NO2 X=-NHg-HC1 Ill-05H 1 19'121 47-47. 4 108. 5-109. 0 43. 0-43. 2 93. 5-95. 5 46. 8-47. 6 59. 0-60. 4

Example 3.4-amin0-1-n-hexyl-Z-pyrrolecarboxylic acid 'Et-hyl 4-amino-1-n-heXyl-2-pyrrolecarboxylate hydrochloride, 5 parts, is added to a solution of potassium hy droxide (83%), 14 parts, in ethanol, 40 parts, and the mixture refluxed 24 hours. To this is added water, parts, and the resulting clear solution is neutralized with hydrochloric acid. The crystalline material which separates is collected, washed with water and dried to give r 3 V 1.3 parts of 4-amino-l-n-hexyl-Z-pyrrolecarboxylic acid having a melting point of 120-121 C.

Example 4.--Ethyl 4-benzamid0-1-n-hexyl-2-pyrr0lecarboxylate Ethyl .4-amino-1-n-hexyl-2-pyrrolecarboxylate hydrochloride, 5 parts, is added to 50 parts of a cold saturated aqueous solution of sodium bicarbonate. To this is added benzoyl chloride, 2 parts, and the. mixture shaken vigorously until a crystalline material separates. The solid product is filtered 01f, Washed well with water and dried to give 5.6 parts of crude product. This is purified by one recrystallization from alcohol to give pure ethyl 4- benzamido-l-n-hexyl-2-pyrrolecarboxylate having a melt ing point of 8586 C.

Example 5..--Methyl 4-amin0-1-n-heryl-2-pyrr0lecarboxylate hydrochloride By following the procedure of Example 1 but substituting absolute methanol for ethanol and refluxing 4 hours instead of 20 minutes, methyl l-n-heXyl-4-nitro-2-pyrrolecarboxylate is obtained. This product has a melting point of 64.264.8 C. after recrystallization from methanol.

The above methyl ester is reduced in the same manner as the ethyl ester in Example 1 to yield methyl 4-amino 1- n-hexyl-Z-pyrrolecarb'oxylate hydrochloride which has a melting point of 116-117" C.

We claim: 1. A compound of the group having the general formula:

No references cited.

U. S. DEPARTMENT OF COMMERCE PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,797,228 June 25, 1957 John S, Webb et :11.

It is hereby certified that error appears in the printed specification 01 the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4, line 13, for "benzyl" read benzoyl Signed and sealed this 25th day of March 1958.,

(SEAL) Atteet:

L KARL mm ROBERT c. WATSON Atteeting Officer Comnissioner of Patents 

1. A COMPOUND OF THE GROUP HAVING THE GENERAL FORMULA: 